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Int J Clin Exp Pathol 2013;6(12):2880-2886

Original Article
Delineation of biological and molecular mechanisms underlying the diverse anticancer
activities of mycophenolic acid

Boying Dun, Heng Xu, Ashok Sharma, Haitao Liu, Hongfang Yu, Bing Yi, Xiaoxin Liu, Mingfang He, Lingwen Zeng, Jin-Xiong She

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou 510530, China; Center for
Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA;
Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, China

Received October 1, 2013; Accepted October 30, 2013; Epub November 15, 2013; Published December 1, 2013

Abstract: Background: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA) which has been widely used for the prevention of
acute graft rejection, is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and
potentially a target for cancer therapy. MPA is known to inhibit cancer cell proliferation and induces apoptosis; however, the underlying
molecular mechanisms remain elusive. Methods: We first demonstrated MPA’s antiproliferative and proapoptotic activities using in vitro studies
of 13 cancer cell lines and a xenograft model. Key proteins involved in cell cycle, proliferation and apoptosis were analyzed by Western blotting.
Results: In vitro treatment of thirteen cancer cell lines indicated that five cell lines (AGS, NCI-N87, HCT-8, A2780 and BxPC-3) are highly
sensitive to MPA (IC50 < 0.5 µg/ml), four cell lines (Hs746T, PANC-1, HepG2 and MCF-7) are very resistant to MPA (IC50 > 20 µg/ml) and the
four other cell lines (KATO III, SNU-1, K562 and HeLa) have intermediate sensitivity. The anticancer activity of MPA was confirmed in vivo using
xenograft model with gastric AGS cell line. Further in vitro analyses using AGS cells indicated that MPA can potently induce cell cycle arrest and
apoptosis as well as inhibition of cell proliferation. Targeted proteomic analyses indicate that many critical changes responsible for MPA’s
activities occur at the protein expression and phosphorylation levels. MPA-induced cell cycle arrest is achieved through reduction of many cell
cycle regulators such as CDK4, BUB1, BOP1, Aurora A and FOXM1. We also demonstrate that MPA can inhibit the PI3K/AKT/mTOR pathway
and can induce caspase-dependent apoptosis. Conclusions: These results suggest that MPA has beneficial activities for anticancer therapy
through diverse molecular pathways and biological processes. (IJCEP1310007).

Keywords: MPA, drug repurposing, cancer, apoptosis, xenograft

Address correspondence to: Dr. Jin-Xiong She, Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia
Regents University, 1120 15th Street, Augusta, 30912, USA. Tel: 706-721-3410; Fax: 706-721-3688; E-mail: jshe@gru.edu